Injection apparatus and method of using same

ABSTRACT

The present invention relates to an apparatus and method for using the apparatus for injecting an agent into a tissue, particularly into thin tissues such as the sclera of the eye. The invention provides an apparatus and method for effectively imbedding a needle into a tissue at a predetermined penetration approach angle and penetration distance thereby reducing the risk of penetrating the full thickness of the tissue. The invention includes a support element and a needle guide platform disposed on the support element with an external support surface and a channel extending therethrough and terminating in an aperture at the support surface. A needle disposed in the channel is axially movable along an axis of injection through the channel. The needle is movable from a first retracted position to an extended position corresponding to the penetration distance, along the axis of injection. The axis of injection forms a penetration approach angle of up to about 60° with a tangent of the support surface at a point of intersection of the axis of injection with the projection of the support surface across the aperture.

[0001] The present application is a continuation-in-part of applicationSer. No. 09/127,919, filed Aug. 3, 1998, the entirety of which is hereinincorporated by reference.

FIELD OF THE INVENTION

[0002] The present invention is directed to a method and apparatus forinjecting an agent into a tissue and, more particularly, to a method andapparatus for injecting an agent into a thin tissue such as the scleraof the eye.

BACKGROUND

[0003] There are two basic mechanisms for delivering exogenous agents,such as drugs and diagnostics, to certain types of body tissues. Themost common is delivery via systemic administration.

[0004] In systemic administration, the agent is introduced into thesystemic, or general, circulation by ingestion, injection, orinhalation. Circulating blood delivers the agent to the target tissue byeither passive or active transport. The advantage to this method is thatsystemic administration, especially by ingestion, is simple. Adisadvantage, however, is that the drug or medicament must be deliveredat relatively high dosages in order to reach the targeted area insufficient quantity. Moreover, the agent is delivered to the entirebody, which can include sites where the agent may cause significant sideeffects. This is especially true for chemotherapeutic agents that tendto be toxic.

[0005] Another significant disadvantage is that certain tissues, such asbrain or eye tissue, do not allow some types of chemicals to transferwell from the blood.

[0006] An alternative to systemic administration is to deliver the drugto the tissue by placing it directly into the tissue or in closeproximity thereto. In order to deliver an agent directly to a specifictissue, there must first be a suitable deposit site. Preferably, thisdeposit site will be in close proximity to the targeted area.

[0007] A general example of this type of direct delivery method, is theinjection of an agent to a site of pain, such as a muscle of the leg orarm or a particular joint. A more specific example of this type ofdirect delivery method is the introduction of slow release,drug-containing biocompatible particle implants directly into theanterior and/or posterior portions of the eye. Generally, these implantshave been delivered into the vitreous humor of the eye via anintravitreal injection. While this is an effective method for deliveringthe agent to the targeted area with a reduced systemic loading, itcarries a significant risk of damage to the tissues in the posteriorportion of the eye. Furthermore, patient compliance for chronicadministration is problematic due to the associated discomfort.

[0008] Another conventional example of this type of delivery to the eyeis eyedrops delivered to the eye. Eyedrops act to deliver drugs directlyto the anterior part of the eye by instillation into the cul de sac. Thedrugs are then moved from the tears of the eye across the cornea andinto the anterior chamber without first entering the systemiccirculation path. The advantage of this mode of delivery is that thedrug is concentrated in the target tissue with a much lower systemicloading. This tends to reduce the above-mentioned systemic effects. Thedisadvantage of this type of administration is that not all tissues areaccessible by this route of administration and tears may also remove asignificant portion of the drug away from the targeted area relativelyquickly.

[0009] Regardless of the method of delivery, drugs and other exogenouschemicals are cleared from any site of injection by a combination ofmechanisms. Among these are: enzymatic degradation; diffusion into thesurrounding tissue; and transport by the systemic circulation. Of these,transport by the systemic circulation is usually the most predominantmechanism. Accordingly, the deposit site should have a relatively lowrate of clearance into the systemic circulation in order to reduce thesystemic loading.

[0010] Many biological tissues, such as some layers of the walls ofblood vessels and fallopian tubes, as well as the sclera of the eye,have relatively few cells and blood vessels and tend to exhibitproperties which make them desirable deposit sites. These types oftissues are composed of intertwined fibers and fluid. As such, they areconsidered porous media in that the areas between the fibers form acontinuous network of “channels” (interstitial space). These tissuesalso exhibit relatively low overall drug clearance rates because thereis little or no enzymatic activity or blood flow, which leaves diffusionas the major elimination mechanism.

[0011] Thus, drugs deposited into these types of tissues will usuallyremain localized to the site of injection longer than in more cellularand vascularized tissues, such as the skin. The problem with thesetissues, however, is that most of them are thin (e.g., from about 0.3 mmup to about 1.5 mm) and present numerous obstacles to injection withinthe thin tissue.

[0012] Generally, when an exogenous fluid is injected into a poroustissue, such as the sclera of the eye, the fluid must displace theendogenous fluid in the channel or interstitial space in the tissue. Therate at which exogenous fluid may be introduced into the tissue isinversely propositional to the resistance caused by the channels. Inaddition, when a needle is placed into a tissue, it creates a fluid pathto the exterior of the tissue along the outer surface of the needle.

[0013] When making an injection, one consideration is the minimizationof the leakage of fluid along this path to the exterior. In consideringthis leakage, it has been found that the resistance to fluid flow alongthe needle path is directly proportional to the length of the needlethat is in contact with the tissue (i.e., length of the needle imbeddedin the tissue). In considering the leakage, it has further been foundthat the ratio of the flow rate along the needle to the flow ratethrough the tissue is inversely proportional to the ratio of therespective resistances. Thus, it would be beneficial to increase theresistance to flow along the needle by increasing the penetrationdistance of the needle into the tissue. However, because of theinaccuracies and inherent variability with human intervention incontrolling the penetration distance of the needle during suchinjections, control over the penetration distance of the needle,especially in thin tissues, presents numerous obstacles.

[0014] In drug delivery to the retinal or choroidal region of the eye,numerous problems may be encountered. For example, with directinjection, choroidal hemorrhaging leading to retinal detachment mayoccur. In addition, with systemic administration, side effects andmolecular size present problems that must be accommodated. Further,topical application to the cul de sac presents transport difficulties.

[0015] In addition, delivery of large molecules or particles (referredto herein as “large agents”), such as anti-bodies, viral vectors and thelike, to the back of the eye (retina and choroid) is very difficultunless an injection is made directly into the vitreous humor of the eye.An alternative to such a method is to pierce the sclera at the back ofthe eye and make an injection directly to the retinal or choroidaltissues. As noted above, such procedures have substantial risk incausing damage to the ocular tissues. Moreover, delivery of these typesof agents from a remote depot, such as the sclera or subconjunctivalspace is problematic because the agents tend to disperse very slowlyfrom the site of injection.

[0016] Various approaches have been proposed to overcome the problems ofinjecting drugs or other therapeutic agents into the retina or choroidalregions. Generally, drugs have been delivered to the retina via thevitreous humor via an intravitreal injection. As noted above, while themethod may be an effective method, it carries a significant risk ofretinal detachment and/or infection. Furthermore, patient compliance forchronic administration is problematic due to the associated discomfort.Therefore, an alternate method of delivery is desirable, especially forthe chronic delivery of either large molecules, such as proteins,antibodies, viral vectors, or drugs that have a high systemic toxicity.

[0017] A proposed method for delivering and withdrawing a sample to andfrom the retina is shown in U.S. Pat. No. 5,273,530 and U.S. Pat. No.5,409,457. This device is for delivering a sample directly to the retinaor subretinal region or withdrawing a sample therefrom. Although thedevice discloses a collar for regulating the depth the tip penetratesinto the intraocular or subretinal region, the collar and tip are notadapted to prevent the penetration of the full thickness of the scleraand the choroid tissues in delivering the samples to the retina. Indeed,the device requires that the sclera and choroid be traversed by the tipprior to delivering or withdrawing the sample from the retina orsubretinal region. Penetration into the choroid and retina can causehemorrhage and possible retinal detachment. Moreover, the user mustmanipulate the tip, or needle through the ocular layers. Such imprecisemovement could cause potential complications during the traversal of theocular layers. Further, the device does not overcome the inaccuraciesand variability which are inherent in injecting into a tissue whereinthe path of the needle and movement of the needle is controlled by humanintervention. Indeed, such inaccuracies may result in piercing theentire thickness of the thin layer tissue resulting in complications ormay present drug delivery problems as described below.

[0018] Injections into thin tissues, such as the sclera of the eye orthe walls of blood vessels, present problems for such a device. Thepenetration distance of the needle into the tissue is limited by thethickness of the tissue, the orthogonal approach of the needle to thetissue surface, and human control of the needle. Indeed, it is difficultfor the user to control the angle and penetration distance of the needlein a free-handed manner, specifically into thin layer tissues.

[0019] For example, the sclera of the human eye generally varies from athickness of about 0.3 mm to about 1.5 mm. Thus, injections made with aneedle that is in a generally orthogonal relationship to the surface ofthe tissue are likely to fail due to fluid leakage from the site ofinjection or piercing the entire thin tissue thereby causingcomplications to underlying tissues or releasing the agent away from thetargeted location.

[0020] In the case of scleral injection, the close proximity of thesclera to the retina means that a significant fraction of any agentinjected into the intrascleral space may reach the retina by passivediffusion. There may be little direct elimination of any agent by eitherenzymatic degradation, clearance into the blood stream, or removal bytears due to the acellular and nonvascular nature of the sclera.Moreover, complications due to damaging the underlying choroid andretinal layers may be eliminated.

[0021] Another area which could benefit from direct injection is thewall of blood vessels especially those with atherosclerotic plaques.While access to the outer surface of many vessels is difficult, accessto the inner surface of the vessel is not, there being a number ofdevices available for that purpose. However, delivery of therapeuticagents directly to these sites is problematic because the high rate ofblood flow within the vessel tends to prevent exogenous agents fromadhering to the inner surface. Systemic administration, while possible,is problematic because the region of tissue that would benefit from thetherapeutic agent is small in relationship to overall size of thevasculature. Thus, the agent must be administered in great excess inorder to achieve therapeutic efficacy.

[0022] The walls of certain blood vessels, especially those of theheart, are generally less than 1 mm thick. Precise placement within thewall is difficult. Insertion of a needle into the vessel wall canperforate the vessel causing hemorrhage into the surrounding tissue. Inthe vessels of the heart, such a perforation can be life threatening.

[0023] Devices for direct administration of fluids to the vasculatureare known in the prior art. These rely on substantially orthogonalapproaches to the inner wall of the vessel, the disadvantages of whichhave already been discussed above. In addition, these devices rely on anexternal reservoir for the medicament. A better method of injectionwhere the needle is inserted farther into the tissue should reduce theamount of medicament that leaks from the site of injection. Furthermore,a device with a medicament reservoir deployed closer to the needle wouldrequire substantially smaller volumes of fluid and therefore less waste.

[0024] Thus, as set forth above, there is a need for an apparatus andmethod that reliably and safely facilitates injecting into a thintissue, for example, the sclera, a therapeutic agent which is deliveredeither directly or allowed to diffuse to the targeted area, for example,the retina. There is a further need for a device that is effective forimbedding a needle in a guided injection at a predetermined penetrationapproach angle and penetration distance within the tissue such that ahydrodynamic seal between the tissue and the needle limits injectedfluids from being expelled from the tissue due to the force of theinjection. Furthermore, there is a need for a method for imbedding theneedle at a penetration distance of greater than at least the thicknessof the tissue without penetrating the full thickness of the tissue layerwhich could cause damage to underlying tissues. Moreover, there is aneed for a safe and effective method and apparatus for delivering largemolecules or particles, or large agents, such as antibodies, viralvectors, and the like, to the back of the eye, for example, the retinaand choroid.

SUMMARY OF THE INVENTION

[0025] Accordingly, the present invention is directed to injectionapparatuses and methods for injecting agents into tissues and, morespecifically, for injecting agents into thin tissues such as the scleraof the eye that substantially obviates one or more of the problems dueto the limitations and disadvantages of the related art.

[0026] One objective of the present invention is to provide a method andapparatus that inserts a needle into the tissue such that the needletravels into the tissue substantially parallel to the tissue surface.This increases the length of the needle that can be imbedded into thetissue. This, in turn, increases the resistance to flow along theimbedded needle and decreases leakage from the site of injection. Thisallows for greater volumes of fluid to be injected and also allows forvariance in human control.

[0027] The invention provides an apparatus and method that reliably andsafely facilitates injecting a therapeutic agent into a thin tissue,such as the sclera of the human eye, which then is allowed to diffuse tothe targeted area, for example, the retina. The invention also providesan apparatus and method for effectively imbedding a needle into a tissuein a guided injection at a predetermined penetration approach angle andpenetration distance sufficient to provide a hydrodynamic seal betweenthe tissue and the needle such as to minimize injected fluids from beingexpelled from the tissue due to the force of the injection. Furthermore,the invention provides an improved method for imbedding the needle insuch a manner that reduces the risk of penetrating the full thickness ofthe tissue which could cause damage to underlying tissues. The inventionalso reduces the inaccuracies and variability, which are inherent inhuman-controlled movements of injection apparatuses.

[0028] Additional features and advantages of the invention will be setforth in the description which follows, and in part will be apparentfrom the description, or may be learned by practice of the invention.The objectives and other advantages of the invention will be realizedand attained by the apparatuses and methods particularly pointed out inthe written description and claims hereof as well as the appendeddrawings.

[0029] The present invention relates to an apparatus for delivering anagent into a tissue. The apparatus includes a support element and aneedle guide platform disposed on the support element. The needle guideplatform has an external support surface and a channel extendingtherethrough. The channel terminates in an aperture at the supportsurface. The apparatus further includes a needle having a first end anda second end. The needle includes a sidewall defining an outlet in saidneedle and an inlet disposed in the needle. The outlet may be defined inthe sidewall itself or at the end of the needle. Preferably, the outletis at the end of the needle for direct injection and at the sidewall for“indirect” injection (as deemed below). The inlet is preferably in fluidflow communication with the outlet.

[0030] In another aspect, the present invention relates to a method forinjection. The method comprises placing a needle into a tissue, whereinthe tissue preferably has a first surface and a second surface defininga tissue thickness. The needle is placed into the tissue at apenetration distance of greater than about the tissue thickness but suchthat even if extended the needle could not intersect the second tissuesurface. The method further includes inserting an agent into the tissuethrough an outlet defined by a sidewall of the needle. The agent isinserted into the tissue through the outlet such that the agent exitingthe outlet is in an orientation towards one of the first and secondsurface of the tissue in said needle when the needle is placed into thetissue.

[0031] In another aspect, the present invention relates to a method forinjecting an agent into a target tissue. The target tissue has a firstsurface and a second surface defining a tissue thickness. The methodpreferably includes disposing a needle in an injection apparatus. Theapparatus preferably includes a support element and a needle guideplatform disposed on the support element. The apparatus further includesan external support surface and a channel extending therethrough. Aneedle is preferably disposed in the channel and movable along an axisof injection through the channel. The needle preferably has a first endand a second end and includes a sidewall defining an outlet in theneedle and an inlet disposed in the needle. The inlet is preferably influid flow communication with the outlet.

[0032] The method further includes placing the needle in fluid flowcommunication with a medicament reservoir. In addition, the methodincludes positioning the injection apparatus adjacent a tissue surface,advancing the needle outwardly through the channel, and imbedding theneedle into the target tissue such that the outlet is adjacent to, andoriented in a direction substantially facing, one of the first andsecond surface of the tissue. The method further includes transferringthe agent into the tissue.

[0033] In another aspect, the present invention relates to an apparatusfor injecting an agent into a tissue. The apparatus includes a supportelement having a distal end and a proximal end. The apparatus furtherincludes a needle guide platform disposed on the distal end of thesupport element. The needle guide platform preferably has an externalsupport surface and a channel extending therethrough, the channelpreferably terminates in an aperture at the support surface.

[0034] The apparatus also preferably includes a needle disposed in thechannel. The needle being axially movable through the channel from aretracted position to an extended position. The needle has a first endand a second end. The needle also includes a sidewall defining an outletin the needle and an inlet disposed in the needle. The inlet is in fluidflow communication with the outlet. The needle preferably extends fromthe aperture when moving from the retracted position to the extendedposition, whereby, an axis of injection of the needle forms an acutepenetration approach angle of up to about 60° with a tangent of thesupport surface at a point of intersection of a longitudinal axis of theneedle with a projection of the support surface across the aperture.

[0035] In another aspect, the present invention relates to an apparatusfor injecting into a wall of a vessel. The invention includes a catheterbody having a distal end, a proximal end, and an inflation passage. Aneedle guide platform is included and disposed on the distal end of thecatheter body and has an external support surface and a channelextending therethrough. The channel terminates in an aperture at thesupport surface.

[0036] The invention further includes an expansion member disposed inthe catheter body near the distal end. The expansion member is in fluidcommunication with the inflation passage.

[0037] In addition, the invention includes a needle disposed in thechannel. The needle is axially movable along an axis of injectionthrough the channel from a retracted position to an extended position.The needle has a front outlet and an inlet rearwardly located relativeto the front outlet. The front outlet is in fluid flow communicationwith the inlet. The needle extends from the aperture when moving fromthe retracted position to the extended position. The needle guideplatform may be disposed about the vessel by inflating the expansionmember such that the needle is extendable from the aperture and into thewall of the vessel and further wherein, the needle moves along the axisof injection which forms a penetration approach angle of up to about 60°with a tangent of the support surface at a point of intersection of theaxis of injection with a projection of the support surface across theaperture.

[0038] In another aspect, the present invention relates to a method forplacing a needle in a tissue. The tissue has a first surface and asecond surface, which define a tissue thickness. The needle is placedinto the tissue from the first tissue surface at a penetration distanceof greater than about the tissue thickness but such that even ifextended the needle could not intersect the second tissue surface.

[0039] In another aspect, the present invention relates to a method forinjecting an agent into a tissue at a point of injection, the tissuehaving a first surface and a second surface. The first surface andsecond surface define a tissue thickness. The invention includes thesteps of disposing a needle in an injection apparatus, which includes asupport element having a distal end and a proximal end. The apparatusfurther includes a needle guide platform disposed on the distal end ofthe support element. The needle guide platform has an external supportsurface and a channel extending therethrough. The channel terminates inan aperture at the support surface. The needle is disposed in thechannel and movable along an axis of injection through the channel froma restricted position to an extended position. The needle has a frontoutlet and an inlet rearwardly located relative to the front outlet. Thefront outlet is in fluid flow communication with the inlet. The needleextends from the aperture when moving from the retracted position to theextended position. The apparatus further includes an actuator foradvancing and retracting the needle through the channel.

[0040] The invention further includes placing the needle in fluid flowcommunication with a medicament reservoir and positioning the injectionapparatus adjacent the tissue such that the support surface is insubstantial contactual relationship with the tissue. The support surfaceis configured to substantially conform to the geometry of the firstsurface of the tissue. The invention further provides for advancing theneedle outwardly through the aperture and imbedding the needle in thetissue. Finally, a medicament is transferred from the medicamentreservoir through the needle and into the tissue.

[0041] As used herein, the phrase “indirect injection” relates generallyto delivery of an agent to a targeted tissue, preferably via injectionof the agent through a cannula, needle, or other suitable device into asecond tissue that is near or in substantial contact with the targetedtissue.

[0042] It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory and are intended to provide further explanation of theinvention as claimed.

[0043] The accompanying drawings are included to provide a furtherunderstanding of the invention and are incorporated in and constitute apart of this specification, illustrate several embodiments of theinvention and together with the description serve to explain theprinciples of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[0044] The accompanying drawings, which are incorporated in andconstitute a part of this specification, illustrate embodiments of theinvention and, together with the description, serve to explain thefeatures, advantages, and principles of the invention.

[0045]FIG. 1a is a sectional elevational view of an exemplary embodimentof the present invention shown with the needle in the retractedposition;

[0046]FIG. 1b is a sectional elevational view of an exemplary embodimentof the present invention shown with the needle in the extended position;

[0047]FIG. 1c is a detailed view of the front outlet of the needle of anexemplary embodiment of the present invention;

[0048]FIG. 1d is a cross-sectional elevational view of an exemplaryembodiment of the present invention taken along line A-A of FIG. 1b;

[0049]FIG. 1e is a partial view of an alternative embodiment forstabilizing the apparatus against the tissue;

[0050]FIG. 1f is a detailed view of an exemplary embodiment of thepresent invention used with intervening layers of tissue;

[0051]FIG. 2a is a sectional elevational view of a second exemplaryembodiment of the present invention shown with the needle in theretracted position;

[0052]FIG. 2b is a sectional elevational view of a second exemplaryembodiment of the present invention shown with the needle in theextended position prior to delivery of the fluid from the medicamentreservoir;

[0053]FIG. 2c is a sectional elevational view of a second exemplaryembodiment of the present invention shown with the needle in theextended position after delivery of the fluid from the medicamentreservoir;

[0054]FIG. 3a is a detailed view of the relationship between the needleguide platform and an exemplary tissue;

[0055]FIG. 3b illustrates an alternative embodiment for a curved needle;

[0056]FIG. 3c is a detailed view of the relationship between the needleguide platform and exemplary multiple layers of tissue;

[0057]FIGS. 4a and 4 b illustrate injection into the sclera region ofthe eye using an exemplary embodiment of the present invention;

[0058]FIGS. 5a-5 c illustrate an alternative embodiment for stabilizingthe apparatus against the tissue;

[0059]FIG. 6a is a sectional elevational view of a third exemplaryembodiment of the present invention;

[0060]FIG. 6b is a sectional end view of the third exemplary embodimentof the invention shown with the needle extended;

[0061]FIG. 6c is a sectional end view of the third exemplary embodimentof the invention shown with the needle retracted;

[0062]FIG. 6d is a partial detailed view of the contour of the supportsurface;

[0063]FIG. 7 is a detailed view of a fourth exemplary embodiment of thepresent invention; and

[0064]FIG. 8 illustrates injection into a tissue using the fourthexemplary embodiment of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0065] Reference will now be made in detail to the present preferredembodiments of the invention, examples of which are illustrated in theaccompanying drawings. The exemplary embodiments of this invention areshown in some detail, although it will be apparent to those skilled inthe relevant art that some features which are not relevant to theinvention may not be shown for the sake of clarity.

[0066] Referring to FIGS. 1a and 1 b, there is illustrated, in aside-elevational sectional view, an exemplary apparatus of the presentinvention and is represented generally by reference numeral 10. Theexemplary embodiment of the apparatus 10 and tissue 50 shown in FIGS.1a-1 d have been expanded in scale in order to provide clarity to thedescription of the invention and should not be construed to place limitson the dimensions or characteristics thereof. Moreover, the apparatus 10and tissue 50 are shown in different scales for added clarity.

[0067] The apparatus 10 includes a support element 12 having a distalend 14 and a proximal end 16. Support element 12 allows a user to graspand position the apparatus with one hand while manipulating the site ofinjection with the other hand. Alternatively, support element 12 may beplaced in a retaining device or other well known support structure inorder to provide increased stability throughout the injection process orto otherwise free up the hand of the user.

[0068] Support element 12 can be made of a metal such as stainless steelor aluminum, or may be made of other suitable materials. Alternatively,support element 12 can be made of plastic. The material from whichsupport element 12 is made is preferably non-irritating to theparticular targeted tissue. Support element 12 can be opaque ortransparent, depending upon the particular application.

[0069] A needle guide platform 18 is disposed on the distal end 14 ofsupport element 12. Preferably, the longitudinal axes of support element12 and the needle guide platform 18 will be in a general parallelrelationship, however, it should be apparent to one of ordinary skill inthe art that the longitudinal axes may be coincidental, or at an angleto each other. This would depend upon the particular application forwhich the device may be directed.

[0070] The needle guide platform 18 has an external support surface 20which is shaped to substantially conform to the surface of the tissueinto which the injection is to be made, as will be described in moredetail below. Needle guide platform 18 may be made of the same materialas support element 12 or may be made of a different material ifrequired. For example, support element 12 may be made of a light,transparent plastic, such as acrylic or other suitable plastic. Whereasneedle guide platform 18 may be made of a material with a highcoefficient of friction against the targeted injection tissue so thatthe device will not slip during use. Materials, such as, but not limitedto, natural or synthetic rubber, may be suitable as would knurled ortextured metals. Alternatively, needle guide platform 18 may be providedwith a mechanism which is intended to impale the tissue, such as pointedprojections 15 (one example of which is shown in FIG. 1e), or togrip/pinch the tissue, such as a tapered groove 17 (shown in FIGS. 5a-5c), so as to hold the tissue 50 in a fixed relationship to the needleguide platform 18.

[0071] Referring to FIGS. 5a-5 c, a tapered groove 17 is shown as partof the needle guide platform 18. The tapered groove 17 may allow for anoverlying tissue, such as the conjunctiva 55 of the eye, to be grippedand/or pinched into the tapered groove 17 as the device is moved alongthe conjunctiva 55 and into position for injection into, for example,the sclera 54 of the eye. This is shown by way of example in FIGS. 5aand 5 c. This may, as noted above, prevent the device from slippingduring the subsequent injection.

[0072] A channel 22 extends along a longitudinal axis through the needleguide platform 18. Channel 22 terminates at the external support surface20 in an aperture 24.

[0073] A needle 26 or other suitable cannula device is disposed in theneedle guide platform 18. Preferably, needle 26 is disposed in channel22 and is movable through channel 22 from a first retracted position toan extended second position along a longitudinal axis 78 of the needle26. The longitudinal axis 78 preferably coincides with the longitudinalaxis of the channel 22. It should be clear to one of ordinary skill inthe art, however, that the longitudinal axis 78 might alternately bepositioned such that it is not coincidental to the longitudinal axis ofchannel 22.

[0074] Needle 26 may be advanced from the first retracted position tothe extended second position by a manual actuator 28 which is axiallymovably disposed on support element 12 and attached to the needle 26.Actuator 28 may rest in a groove (not shown) in support element 12 ormay be attached for axial movement in any well known manner. Actuator 28may include a handle 30 connected at a rear extremity of actuator 28 forreceiving an external actuating force directly from an operator of theapparatus 10. Other mechanisms such as a compressed gas/pistonarrangement or a compression spring mounted to support element 12 may beused to provide the external actuating force to the needle 26. Thesemechanisms may likewise be externally riggered by the operator.

[0075] Needle 26 preferably comprises a first needle section 26 a and asecond cannula section 26 b. Second section 26 b may be either rigid,flexible, or a combination of the two. Alternatively, needle 26 maycomprise a single needle section having a constant diameter. Firstsection 26 a is, however, preferably of a larger gauge (and thus of asmaller diameter) than second section 26 b. For example, first section26 a may be 33 or 30 gauge and second section 26 b may be 22 gauge. Ingeneral, it should be understood by one of ordinary skill in the artthat first section 26 a may be in the range of from about 26 gauge to 37gauge, and second section 26 b may be in the range of from about 12gauge to about 22 gauge. It should be understood, however, that otherneedles of different gauge size may be suitable, depending on theparticular tissue, patient and procedure, or depending on thephysician's preference and needs. Generally, the diameter of the needle26 will be less than the thickness of the targeted tissue 50. Sections26 a and 26 b may be joined by any well known method, for example, butnot limited to, soldering or welding. Alternatively, sections 26 a and26 b may be joined by a threaded connection or a detachable fitting suchas a separate threaded connector.

[0076] In order to deliver, or inject, agents into the tissue 50, needle26 is hollow and has a front outlet 32 (shown in FIG. 1c) in fluid flowcommunication with an inlet 34 rearwardly located relative to frontoutlet 32. Generally, the lumen, or hollow space of the needle 26, mustbe large enough to permit flow of relatively viscous agents or fluidswithout undue force being applied. In the exemplary embodiment shown inFIGS. 1a and 1 b, inlet 34 is located at the rear portion of secondsection 26 b of needle 26. It should be understood that inlet 34 may belocated at any location along needle 26, such as the side of needle 26.Furthermore, it is preferable to have the distance between inlet 34 andoutlet 32 as short as practical so that fluid retention between theinlet 34 and outlet 32 may be kept to a minimum.

[0077] As further shown in FIGS. 1a, 1 b, and 1 d, a groove 36 extendsalong an interior depressed rearward portion the needle guide platform18. A flange member 38 having an outer flange portion 40 and a bodyportion 42 is axially movably disposed in groove 36. Flange member 38 ispreferably rigidly connected to the needle 26 by any method well knownin the art. Groove 36 may be semi-circular in shape as shown in FIG. 1dand flange member 38 may be circular in shape. However, it should beunderstood by one skilled in the art that other shapes may be used, forexample, but not limited to, square or rectangular. Flange member 38 isconfigured to limit the distance needle 26 extends from support surface20 through aperture 24 as will be described in more detail below. Forexample, flange member 38 may be attached to the needle 26 at adifferent location, however, this location must not permit the needle 26to extend from the support surface 20 when the needle 26 is in the firstretracted position.

[0078] A medicament reservoir 44 containing a therapeutic agent which isto be delivered, or injected, into tissue 50, is connected to the inlet34 of needle 26 through a conduit 46. Conduit 46 may be any well knowntubing or other mechanism for fluid transport. Preferably, conduit 46will be flexible and will thereby provide full mobility to the operator.As shown in FIGS. 1a and 1 b, preferably conduit 46 will be flexibletubing. Conduit 46 is in selective fluid flow communication with thehollow passage through needle 26 via inlet 34 to deliver the therapeuticagent to the front outlet 32 of needle 26 and thereafter into thetargeted tissue 50. A predetermined amount of the therapeutic medicamentor fluid may be delivered in response to, for example, the manualoperation of a switch (not shown) to drive a pump 48, such as a syringepump, which pumps into conduit 46 the desired amount of medicament orfluid. The medicament reservoir 44 supplies the medicament or fluid topump 48.

[0079] Reference will now be made to the operation of the apparatus 10,specifically as shown in FIGS. 1a and 1 b, in order to more clearlydescribe the interrelationship among the individual elements as well asthe overall injection cycle. Referring first to FIG. 1a, the apparatus10 is shown generally in contactual relationship, via support surface20, with a tissue 50 (enlarged in scale). If, however, one or moreintervening layers of tissue separates the target tissue 50 from theapparatus 10, the apparatus 10 would be in general contactualrelationship with the outer most layer of tissue. The needle 26 is inthe retracted position (i.e., needle section 26 a is not extending fromthe aperture 24 of support surface 20). The flange member 38 is disposedin the proximal end of the groove 36.

[0080] Once the apparatus 10 is placed in the desired location withregard to tissue 50, and specifically that the support surface 20 is insubstantial contactual relationship with and stabilized against thetissue 50 (or an intervening layer of tissue), an operator may move orslide handle 30 of actuator 28 in the general axial distal directionalong support element 12. This will cause the needle 26, as will bedescribed immediately hereinafter, to be advanced from the retractedposition of FIG. 1a to an extended position as shown in FIG. 1b.

[0081] As the handle 30 is moved by the user in the axial directionalong support element 12, flange member 38 moves in the axial distaldirection along the groove 36 which correspondingly moves the attachedneedle 26 in the axial direction along the channel 22 of needle guideplatform 18. The forward or distal axial movement of the needle 26 andthe flange member 38 continues until the forward face of the outerflange portion 40 contacts the raised portion 25 of groove 36. At thispoint the flange member 38 has moved a distance y (as shown in FIG. 1a)and the needle 26 has extended forwardly from the aperture 24 of thesupport surface 20 and into the tissue 50 by a corresponding penetrationdistance y. As shown in FIG. 1f, if one or more layers of tissueseparates the target tissue 50 from the apparatus 10, the correspondingpenetration distance would be y minus the thickness of the interveninglayer or layers of tissue 100 at the point of insertion x. It should beapparent that the penetration distance may be specifically chosen forvarious applications and corresponding changes to the attachment offlange member 38 onto needle 26 could be made to accommodate thetargeted penetration distance.

[0082] As shown in FIG. 1b, the forward face of the outer flange portion40 of flange member 38 is in contact with the raised portion 25 ofgroove 36. Thus, forward axial movement of the needle 26 is impeded. Theuser may at this time separately engage a switch (not shown) to drivepump 48. Pump 48, in response to the switch, delivers the desired volumeof fluid or medicament from the medicament reservoir 44 through theconduit 46, through the needle 26, and thereafter into the targeted siteof injection within tissue 50.

[0083] Following injection of the fluid in the manner described above,the user may normally slide or move the handle 30 in the proximal axialdirection along support element 12 which will in turn move the flangemember 38 and the needle 26 in the corresponding direction. The user maycontinue to move the handle 30 in the proximal axial direction until theproximal end of the body portion 42 of the flange member 38 contacts therearward wall 41 of channel 22. At this point and because of theparticular dimensions for the elements, particularly the flange member38, chosen for the specific application, the needle 26 will be safelyretracted within the needle guide platform 18 and the apparatus 10 maybe withdrawn away from the tissue 50 and/or any intervening layers oftissue. Alternatively, the user may pull the needle 26 directly out ofthe tissue 50.

[0084] Referring to FIGS. 2a through 2 c, there is shown a secondexemplary embodiment of the present invention. Corresponding referencenumerals will be used where appropriate.

[0085] The second exemplary embodiment is represented generally byreference numeral 13. The exemplary embodiment of the apparatus 13 andtissue 50 shown in FIGS. 2a-2 c have been expanded in order to provideclarity to the description of the invention and should not be construedto place limits on the dimensions or characteristics thereof. The secondembodiment may also be used with intervening layers of tissue betweenthe apparatus 13 and the target tissue 50. For clarity, the secondembodiment will be explained without reference to intervening layers.One skilled in the art, however, will appreciate that the otherembodiments may be used with multiple layers of tissue. Moreover, theapparatus 13 and tissue 50 are shown in different scales for addedclarity.

[0086] Apparatus 13 has a support element 12 (shown in partial view)with a needle guide platform 18 disposed thereon. As noted above,preferably, the longitudinal axes of support element 12 and the needleguide platform 18 will be in a general parallel relationship, however,it should be apparent to one of ordinary skill in the art that thelongitudinal axes may be coincidental, or at an angle to each other.This would depend upon the particular application for which the devicemay be directed.

[0087] Needle guide platform 18 includes an external support surface 20that is shaped to substantially conform to the surface of the tissue 50into which the injection is made. Needle guide platform 18 furtherincludes a guide channel 22 disposed therein. Channel 22 preferablyincludes a proximal section 22 a and a distal section 22 b. Distalsection 22 b is preferably of smaller cross-sectional area than proximalsection 22 a and terminates at the external support surface 20 in anaperture 24. Proximal section 22 a and distal section 22 b may be of anypractical shape and/or cross-section, however, each section ispreferably cylindrical in shape and therefore circular in cross section.

[0088] A medicament reservoir 44 is axially movably disposed in thedistal section 22 b of channel 22. Preferably, medicament reservoir 44is cylindrical in shape, however, any other well-known and practicalshape may be used, for example, but not limited to, square ortriangular. The medicament reservoir 44 has a housing or body 45 and apiston 47 sealingly axially movable therein for defining a variablevolume chamber 49. Piston 47 may be formed of a suitable elastomer orother suitable material for sealing contact with the body 45 of themedicament reservoir 44. A tubular needle 26 is attached at its proximalend to the medicament reservoir 44 and is in fluid flow communicationtherewith.

[0089] An actuator 28 is axially movably disposed, in part, in thechannel 22 of the needle guide platform 18 and extends through theproximal end thereof and, in part, in the support element 12, as shownin FIGS. 2a-2 c. In the exemplary embodiment shown in FIGS. 2a-2 c,actuator 28 includes a rod or shaft 77 having a plunger 29 disposed onthe distal end of shaft 77 and an extension arm 31 disposed on theproximal end of shaft 77. A helical compression spring 35 is disposed onthe portion of shaft 77 which is disposed in channel 22 of needle guideplatform 18 and is interposed between the plunger 29 and the rearwardwall 37 of channel 22. Extension arm 31 preferably extends generallyperpendicular from shaft 77 to the exterior of support element 12 and isfree to move in a slot (not shown) through support element 12 as theshaft 77 moves in a general axial direction as will be explained in moredetail below. Preferably, a tab 33 or other suitable mechanism isdisposed on the opposite end of the extension arm 31 to allow a user toretract the shaft 77 and consequently the needle 26 following injectionas will be explained in more detail below.

[0090] A trigger 64, which may be a button or other suitable device, isdisposed on the exterior of the needle guide platform 18. Trigger 64 maybe attached in a well-known manner to a first end 71 of a lever 66.Lever 66 is configured to pivot about a pin 70 or other suitablemechanism. A second end 72 of lever 66 preferably has a cam surface 73and a flat or planar surface 74 which may be in substantial engagementwith the plunger 29 when the needle 26 is in the retracted position asshown in FIG. 2a. Trigger 64 can activate release by other methodswell-known in the art.

[0091] Reference will now be made to the operation of the apparatus 13in order to more clearly describe the interrelationship among theelements as well as the overall injection cycle. Referring first to FIG.2a, the apparatus 13 is shown generally in contactual relationship, viasupport surface 20, with a tissue 50 (enlarged in scale for clarity).The needle 26 is in the retracted position (i.e., not extending fromaperture 24 of support surface 20). The medicament reservoir 44 isdisposed in the proximal end of the channel 22. The second end 72 oflever 66, and more particularly, the planar surface 74, is insubstantial engagement with the plunger 29 prohibiting axial movementthereof and holding the spring 35 in a compressed state. Furthermore,the piston 47 is disposed in the proximal end of housing 45.

[0092] After the apparatus 13 is in the desired location with regard tothe tissue 50 and particularly that the support surface 20 is insubstantial contactual relationship with and stabilized against thetissue 50, an operator may depress trigger 64 which will cause theneedle 26, as will be described immediately hereinafter, to be advancedfrom the retracted position of FIG. 2a to an extended position as shownin FIG. 2b.

[0093] As the trigger 64 is depressed by the user, the lever 66 rotatesabout pin 70 which causes the second end 72 of lever 66 to slidablydisengage the plunger 29 of actuator 28. This, in turn, releases thecompression spring 35 which causes the plunger 29 to move in a forwardor distal axial direction. Compression spring 35 may alternately be anycompression mechanism which will provide a force to drive plunger 29 inthe forward axial direction. Plunger 29 contacts piston 47 and moves themedicament reservoir 44 in the axial direction along the proximalsection 22 a of channel 22 which correspondingly moves the attachedneedle 26 in the axial direction along the distal section 22 b ofchannel 22. The forward axial movement of the needle 26 and themedicament reservoir 44 continues until the forward end of housing 45contacts the forward wall portion 53 of channel 22. At this point themedicament reservoir 44 has moved a distance x (as shown in FIG. 2a) andthe needle 26 has extended forwardly from the aperture 24 of the supportsurface 20 and into the tissue 50 by a corresponding penetrationdistance, x. It should be apparent that the penetration distance may bespecifically chosen for various applications and corresponding changesto the dimensions of the elements, for example, but not limited to, themedicament reservoir 44 and the channel 22 could also be made toaccommodate the chosen penetration distance. It should also beunderstood by one of ordinary skill in the art that the force requiredto axially move the medicament reservoir 44 and the needle 26 within thechannel 22 is less than the force required to move the piston 47 whichis sealingly disposed in housing 45 of the medicament reservoir 44.

[0094] As shown in FIG. 2c, the medicament reservoir 44 is in contactwith the forward wall portion 53 of channel 22. Thus, forward axialmovement of the needle 26 and the medicament reservoir 44 is impeded.Plunger 29, however, continues to move forward due to the extension ofspring 35 and overcomes the resistive force of the sealingly disposedpiston 47 in housing 45 of the medicament reservoir 44. As piston 47moves in the forward axial direction it forces the volume of fluid ormedicament 76 through the needle 26 and into the targeted site ofinjection within tissue 50.

[0095] Following injection of the fluid in the manner described above,the user normally may slide tab 33 in the proximal axial directionagainst the force of the spring which will in turn move the medicamentreservoir 44 and the needle 26 in the corresponding direction. Asplunger 29 axially slides in the proximal direction it contacts the camsurface 73 of the second end 72 of lever 66 causing the lever 66 torotate about pin 70 in a counterclockwise position (in relation to FIGS.2a-2 c). At the same time, spring 35 is compressed by the plunger 29. Asthe plunger 29 moves past the second end 72 of lever 66, the lever 66rotates in a general clockwise direction such that the planar surface 74of lever 66 returns to substantial engagement with the plunger 29 asoriginally shown in FIG. 2a. Alternatively, the user may pull the needle26 directly out of the tissue 50.

[0096] It should be understood by one skilled in the art that variousactuator mechanisms may be employed in the invention. For example, theplunger 29 may alternatively be connected to a source of compressed gaswith a valve which may be actuated by the trigger 64. Alternatively, theplunger 29 may be actuated by the user. Likewise, separate actuatorassemblies could be employed in order to achieve extension of the needle26 and movement of the fluid within the medicament reservoir 44 andthrough the needle 26 to the targeted site of injection.

[0097] Reference will now be made to FIG. 3a, where a detailed view ofthe support surface 20 is shown in relationship to a representativetissue of the human body 50. As can be seen in FIG. 3a, and as describedabove, support surface 20 is configured to substantially contact thesurface of the tissue 50. Tissue 50 includes an outer surface 51 and aninner surface 52. Outer surface 51 and inner surface 52, together definea tissue thickness, t, as shown in different scale to the needle guideplatform portion 18 of apparatus 10 in FIG. 3a.

[0098] It should be understood by one of ordinary skill in the art thatthe apparatus 10 of the present invention has application to a widevariety of tissues 50, especially to thin layer tissues withconfigurations of varying radii of curvatures. Moreover, the spirit ofthe invention may also include flat tissues. Among the many biologicaltissues that the present invention is particularly suited to, but notlimited to, are some layers of the walls of blood vessels and fallopiantubes, as well as the sclera of the eye.

[0099] Injections into tissue 50, especially of the thin layer tissuetype, may be limited by the thickness t, defined by the outer surface 51and the inner surface 52, as well as the radius of curvature r. Thethickness t could range from about 0.3 mm to about 1.5 mm, in the caseof the sclera of the human eye. The predominant limitation to such thinlayer injections is the leakage which normally occurs along the needle26 to the outer surface 51 due to insufficient penetration distance ofthe needle 26 into the thin tissue 50. Another limitation is theinability to stabilize the device against the targeted tissue 50,especially those tissues having small radii of curvature r, in order toprovide a guided injection route and prevent errors due to humanmanipulation. In addition, tissue pliability or flexibility haspresented numerous problems with regard to human control over thepenetration distance of the needle and control over the overallplacement of the needle in the targeted deposition site.

[0100] The exemplary embodiment, as shown in FIG. 3a and previouslydescribed above, overcomes these limitations. First, inserting theneedle 26 at a penetration approach angle a, which will be discussed inmore detail below, allows the needle 26 to travel roughly parallel tothe outer surface 51 of the tissue 50. The needle 26 is placedsubstantially between the outer surface 51 and the inner surface 52, andmore particularly, preferably midway between the outer surface 51 andthe inner surface 52. This positioning increases the penetrationdistance of the needle 26 into the tissue 50 sufficiently to reduceleakage and, for example, to at least greater than the tissue thicknesst, as will be described in more detail below.

[0101] As can be seen in FIG. 3a, for an embodiment with a straightneedle, the axis of injection 27 coincides with the longitudinal axis ofthe needle 26. The axis of injection 27 intersects the projection ofsupport surface 20 across aperture 24. This intersection of the axis ofinjection 27 and the projection of support surface 20 across aperture 24defines a point P. A tangent T-T may be defined at point P for thesupport surface 20 in a well known manner. Tangent T-T and the axis ofinjection 27, together, define the penetration approach angle α. Angle αis measured in the plane defined by tangent T-T, the axis of injection27 and a line drawn perpendicular to tangent T-T at point P. It shouldbe apparent to one of ordinary skill in the art that support surface 20may comprise varying shapes, for example, but not limited to, curved orplanar, in order to substantially conform to the shape of the targetedtissue 50 when support surface 20 is brought into substantial contactwith the outer surface 51 of tissue 50. Regardless of the shape ofsupport surface 20, one may define tangent T-T at the intersection pointP in the well-known manner. If support surface 20 is planar, then itshould be understood that tangent T-T generally coincides with supportsurface 20 and intersection point P may be defined at the intersectionof the axis of injection 27 and the projection of support surface 20across aperture 24.

[0102] Alternatively, it should be understood by one skilled in the artthat the spirit of the invention may include a curved needle 26 disposedin a curved channel 22 for movement therethrough. An exemplaryillustration of such an embodiment is shown in partial view in FIG. 3b.As can be seen in FIG. 3b, the longitudinal axis 78 of needle 26 iscurved to preferably correspond to the curved axis of the curved channel22. Needle 26 is movable along the curved longitudinal axis 78. Thelongitudinal axis 78 intersects the projection of support surface 20across aperture 24. This intersection of the longitudinal axis 78 andthe projection of support surface 20 across aperture 24 define a pointP. A tangent T-T may be defined at point P′ for the support surface 20in a well-known manner. Additionally, the axis of injection for a curvedneedle 26 may be defined as a second tangent T′-T′ at point P′ for thecurved longitudinal axis 78 of needle 26. Together, tangent T-T and theaxis of injection 27 (T′-T′) define the penetration approach angle α.Angle α is measured in the plane defined by tangent T-T and T′-T′, thelongitudinal axis 78 and a line drawn perpendicular to tangent T-T atpoint P′. It should be apparent to one of ordinary skill in the art thatsupport surface 20 may comprise varying shapes, for example, but notlimited to, curved or planar, as described above.

[0103] As noted above and illustrated in FIG. 1f, the invention may alsobe used if intervening layers of tissue 100 separate the apparatus 10and the target tissue 50. FIG. 3c shows the needle guide platform 18portion of apparatus 10 with a straight needle and used with multiplelayers of tissue 100, 50. The penetration approach angle is determinedas discussed above. Moreover, the alternate embodiments, including acurved needle shown in FIG. 3b, may also be used with intervening layersof tissue 100.

[0104] The minimum penetration distance of needle 26 that is needed toprevent leakage of a specific fluid or agent from a specific tissue maybe estimated from the permeability and elastic properties of theparticular tissue and the viscosity of the particular fluid or agent.The permeability of the tissue can be measured for porous media usingrelatively simple and well known experimental methods, such as thosedescribed in Fatt and Hedbys, Exp. Eye Res., Vol. 10, p. 243 (1970), theentirety of which is herein incorporated by reference.

[0105] For a desired imbedded penetration distance, there will be arange of penetration approach angles over which needle 26 may beinserted. The penetration approach angle α chosen for any specificapplication is governed by several factors. Among these are: thepermeability of the particular tissue; the viscosity of the particularfluid or agent; the thickness t and radius of curvature r of the tissue50; the size of the needle 26; and susceptibility to human error.

[0106] Generally, given all of the factors which can affect thepenetration approach angle α for any specific application, a penetrationapproach angle α of up to about 60° is generally preferred. Such a rangegenerally provides for a needle penetration distance at which leakagefrom the site of injection is minimized, if not eliminated, andpotential for perforating the full width of the tissue (i.e., the innersurface) is eliminated. In addition, such a range virtually eliminatesthe variable of tissue pliability or flexibility and its effects uponcontrol of needle placement within the tissue. Moreover, such a rangeprovides application to a wide variety of tissue shapes, includingnearly flat tissue surfaces.

[0107] Referring to FIGS. 4a and 4 b, an apparatus 10, shown inmagnified detail view and similar to the exemplary embodimentillustrated in FIGS. 2a-2 c, is shown in relationship to the sclera 54of human eye. The sclera 54 of the human eye (shown not to scale inFIGS. 4a and 4 b) has a thickness t ranging from about 0.3 mm near theequator of the eye to about 1.5 mm, defined by the outer surface 60 andinner surface 62. The sclera 54 covers the choroid 56 and the retina 58.As can be further seen in FIGS. 4a and 4 b, support surface 20 isconfigured and shaped to conform to the outer surface 60 of the sclera54 which is ultimately defined by the radius of curvature of the ocularglobe or eye 11 of a typical human. Generally, the sclera 54 of thehuman eye has a radius of curvature of approximately 1.2 cm.

[0108] In order to imbed the needle 26 into the sclera 54 such that asufficient hydrodynamic seal is formed between the needle 26 and thesclera 54 thereby minimizing leakage of the therapeutic fluid or agent,the penetration distance of the needle 26 may be approximately in therange of preferably about 1.5 mm to about 4 mm. More preferably, thepenetration distance will be in the range of about 2 mm to about 3 mm.

[0109] Given the radius of curvature and permeability of the sclera 54,the viscosity of the fluid or agent to be injected, and the targetedpoint of injection into and within the sclera 54, needle 26 maypreferably be inserted at an approximate penetration approach angle α ofabout 30°. Taking into consideration the variability in the thickness ofthe sclera along the circumference of the eye, the appropriate placementof the fluid or agent into the sclera, and human operator error, apreferred range for the penetration approach angle a for injection intothe sclera may be from about 20° to about 40°.

[0110] It may be necessary or desired to increase the penetrationdistance of needle 26 in order to provide, for example, but not limitedto, more secure sealing or to inject at a particular position within thesclera 54. In order to accommodate such an increase in the penetrationdistance, a correlative change to the penetration approach angle mayalso be required.

[0111] Referring to FIGS. 6a-6 c, a third exemplary embodiment of thepresent invention is shown. The third exemplary embodiment of theapparatus is represented generally by reference numeral 80. Apparatus 80has a catheter body 81 with a guide channel 8 extending therethrough.

[0112] The catheter body 81 includes an external support surface 5 whichis shaped to substantially conform to the surface of the tissue 50 intowhich the injection is to be made. An actuator 19 is disposed in thecatheter body 81 and is connectable to a piston or plunger 7 for movingthe plunger 7 along guide channel 8. It should be understood by oneskilled in the art that actuator 19 may be manually or automaticallyoperated, for instance by a controller 21 connected to actuator 19. Itshould also be understood by one skilled in the art that variousactuator mechanisms may be employed in the invention. For example, theactuator 19 may be a gas/piston arrangement, a compression spring, orother suitable and practical device for moving piston 7 along guidechannel 8.

[0113] A needle 4 or other suitable cannula device is disposed in thecatheter body 81 in a curvilinear channel 23 (as shown in FIGS. 6b and 6c). Needle 4 is movable through channel 23 from a first retractedposition to an extended position. The needle 4 may be advanced from theretracted position to the extended position by the actuator 19 and thepiston 7 as will be described in more detail below. Needle 4 may beeither preformed into a curvilinear shape, flexible, or a combination ofthe two.

[0114] Needle 4 preferably is connected at its proximal end to, and isin fluid flow communication with, a conduit 3. The conduit 3 is likewisepreferably attached at its proximal end to a collapsible medicamentreservoir 6. Collapsible reservoir 6 is preferably made of an elastic,bellows-like material such as rubber or plastic. Alternatively, itshould be apparent to one of ordinary skill in the art that the needle 4may be connected to a remote medicament reservoir through an extendedconduit such as flexible tubing or other suitable mechanism.

[0115] As shown in FIG. 6d, a balloon 1, or other expansion member, ispreferably disposed on the catheter body 81. According to the particularapplication of the apparatus, a balloon 1 may or may not be required.Balloon 1 is in fluid flow communication with an inflation conduit 9 forreceiving an inflation fluid from a fluid source (not shown).

[0116] Reference will now be made to the operation of the apparatus 80,specifically as shown in FIGS. 6a-6 d, in order to more clearly describethe interrelationship among the individual elements as well as theoverall injection cycle.

[0117] The apparatus 80 and more particularly the catheter body 81 isintroduced into the lumen of a vessel, for example the fallopian tubes,in a well known manner. The external support surface 5 is brought intoclose proximity with the targeted site of injection into tissue 50. Oncethe catheter 81 is in the desired location, the fluid source may beactivated by the user which causes an amount of fluid to flow throughinflation conduit 9 and thereafter to balloon 1. Balloon 1 expands inresponse to the fluid and acts to move the support surface 5 intosubstantial contactual relationship to the tissue 50 thereby conformingthe tissue 50 to the contour of support surface 5.

[0118] Once the tissue 50 is conformed to the contour of support surface5, an operator may activate the actuator 19 which in turn moves theplunger or piston 7 along the guide channel 8. This causes the needle 4to move along the curvilinear channel 23 a preset distance such that theneedle 4 may be imbedded into the tissue 50 at the desired penetrationdistance. Subsequent displacement of the plunger or piston 7 deforms thereservoir 6 causing fluid contained therein to be displaced throughneedle 4 and into the tissue 50.

[0119] Following injection of the fluid in the manner described above,the needle 4 may be retracted by reversing the above-described processand the catheter body 81 removed from the lumen of the vessel.Alternatively, it should be understood by one skilled in the art thatmultiple injections may be made.

[0120] An alternative embodiment of the present invention is shown inFIG. 7. As shown, needle 26 preferably comprises a single needle section700 having a first end 700 a and a second end 700 b. Needle section 700additionally includes a sidewall 705. Sidewall 705 defines an outlet 710in needle 26. In a preferred embodiment, sidewall 705 defines outlet 710near or adjacent first end 700 a of needle 26. It should be apparent toone of ordinary skill in the art, that outlet 710 may be defined at aplurality of locations along needle 26. An inlet 720 is also disposed inneedle 26. Inlet 720 can likewise be disposed near or adjacent secondend 700 b in needle 26. As noted above, inlet 720 can be formed insidewall 705. However, it is preferred that inlet 720 be formed in theend of first end 700 a, as shown in FIG. 7. It is also preferred thatinlet 720 be in a substantial co-linear relationship with a longitudinalaxis Z-Z of the lumen, or hollow space extending through needle 26 asshown in FIG. 7. In the present exemplary embodiment, it is preferredthat needle 26 be used as part of the injection apparatus describedabove, but it should be understood by one of ordinary skill in the artthat it is not limited to such use.

[0121] Needle 26 also preferably includes a sharpened point or tip 730preferably disposed on first end 700 a. It should be apparent to one ofordinary skill in the art that sharpened point 730 can be formedintegral with needle 26 in a well-known manner or can be attached toneedle 26 using any well-known technique. It should also be apparent toone of ordinary skill in the art that sharpened point 730 can compriseany number of shapes, including, but not limited to triangular orconical, as shown in FIG. 7.

[0122] As also shown in FIG. 7, it is preferred that outlet 710 be in asubstantial non co-linear relationship with inlet 720 to allow an agentto be directed towards one surface of a targeted tissue as will bedescribed in more detail below. It should be apparent to one of ordinaryskill in the art that outlet 710 could be arranged in a plurality ofconfigurations on needle 26 to accommodate the preferred non co-linearrelationship, including but not limited to, for example, defining outlet710 on an angled surface of sharpened point 730. In addition, it shouldbe understood by one having ordinary skill in the art that a pluralityof outlets 710 could be defined by sidewall 705 and that the pluralityof outlets 710 could be configured in a plurality of arrangements,including, but not limited to, linearly along needle 26 or in an angularrelationship around the circumference of needle 26.

[0123] Turning now to FIG. 8, needle 26 is shown imbedded in a tissue50, such as the sclera of the eye. Tissue 50 includes a first surface 51and a second surface 52. As noted above, a plurality of tissues can beadjacent tissue 50. Exemplary tissues can include, but are not limitedto, a choroid 56 and retina 58 of the eye. As described above, needle 26is preferably imbedded into tissue 50 at a penetration approach anglethat allows a penetration distance into tissue 50 which is sufficient tominimize leakage of the agent. As noted above, needle 26 is preferablyimbedded into tissue 50 to at least greater than the tissue thickness,t.

[0124] In general, three basic factors influence the effectiveness ofindirect injection. These factors include: the direction of agent flow(depicted as arrows R) from needle 26 in relation to a targeted surfaceof tissue 50, which is surface 52 in FIG. 8; the distance of outlet 710from surface 52; and the velocity of the agent as it leaves needle 26through outlet 710. It has been found that the exemplary embodimentshown in FIGS. 7 and 8, is extremely effective for accomplishingindirect injection of an agent to an underlying tissue, such as theretina 58 of the eye.

[0125] Indeed, as shown in FIG. 8, when injecting into the choroid 56 orretina 58 from tissue 50, such as the sclera, outlet 710 is preferablyplaced as close as possible and in a substantial orientation towards thetargeted surface 52. The closer outlet 710 is located to surface 52, thegreater the efficiency of the injection process. In other words, thecloser outlet 710 is to surface 52, the greater the fraction of thetotal delivered agent that reaches the targeted tissue, for example, thechoroid 56 or retina 58. Moreover, the geometry of outlet 710 also playsan important role in the efficiency of the injection. Generally, thesmaller the outlet 710 is, the greater the agent velocity will be for afixed volumetric flow rate.

[0126] Examples using the exemplary embodiments described above areprovided herein below. It should be understood by one having skill inthe art that the following examples serve to illustrate the presentinvention and should not be considered to limit the scope of the presentinvention.

EXAMPLE 1

[0127] A 33-gauge needle having an orifice of 100 microns was placed inthe scleral tissue of the eye at a depth of greater than about thescleral thickness with the outlet of the needle oriented towards theinside surface of the sclera. An injection of 10 microliters of a 1%fluorescein dye solution at a rate of about 1 to 4 microliters/second,and using the technique described above produced, immediate staining ofthe retinal tissue. This staining occurred without the sharpened pointof the needle penetrating through the sclera. The time required forstaining of the retinal region was less than had previously beenobserved from staining resulting from diffusion of the fluorescein fromthe site of injection. In addition, when subsequent trials wereperformed with the outlet of the needle oriented towards the externalsurface (i.e., the surface opposite the choroid and retina) of thesclera, no immediate staining was observed. Therefore, it was concludedthat the fluorescein dye solution was being delivered by convection fromthe outlet of the needle directly to the retina.

EXAMPLE 2

[0128] In another experiment, a 33-gauge needle having a 100 micronorifice was used to deliver large agents, for example, collodial carbonand virus particles, both of which are particulate suspensions in therange of 50 to 150 nanometers in diameter, directly to tissuesunderlying the sclera, such as the retina, without fully penetrating thesclera. Delivery of the collodial carbon particles was at a rate ofabout 1 to 4 microliters/second. Delivery of the virus particles wascarried out at a rate of about 4 microliters/second. Previousexperiments revealed that agents such as these tend to diffuse veryslowly from the site of injection due to their large size. However, inthe case of this experiment, the agents were found in the underlyingtissues much earlier than could be explained by diffusion through thesclera.

EXAMPLE 3

[0129] A 33-gauge needle having a 100 micron orifice was placed in thescleral tissue of the eye at a depth of greater than about the scleralthickness with the outlet of the needle oriented towards the insidesurface of the sclera. An adenovirus vector containing the gene forgreen fluorescent protein (GFP) was injected at a rate of about 4microliters/second at a multiplicity of infection of 0.6. Delivery ofthe viral vector was verified by demonstrating that the cells of thechoroid and retina expressed the GFP. Such expression within the choroidor retina cannot be accomplished without being transected by the virus.

[0130] Conclusion

[0131] While various embodiments of the present invention have beendescribed above, it should be understood that they have been presentedby way of example only, and not limitation. Thus, the breadth and scopeof the present invention should not be limited by any of theabove-described exemplary embodiments, but should be defined only inaccordance with the following claims and their equivalents.

We claim:
 1. An apparatus for delivering an agent into a tissue, theapparatus comprising: a support element; a needle guide platformdisposed on said support element and having an external support surfaceand a channel extending therethrough, the channel terminating in anaperture at the support surface; a needle having a first end and asecond end, said needle including a sidewall defining an outlet in saidneedle and an inlet disposed in said needle, the inlet being in fluidflow communication with the outlet.
 2. An apparatus according to claim 1, wherein said needle is axially movable through said channel from aretracted position to an extended position.
 3. An apparatus according toclaim 2 , further comprising: an actuator for moving said needle throughsaid channel from the retracted position to the extended position.
 4. Anapparatus according to claim 1 , further comprising: a medicamentreservoir disposed on said support element and in fluid flowcommunication with the inlet of said needle.
 5. An apparatus accordingto claim 1 , wherein the external support surface is shaped tosubstantially conform to an external surface of a sclera of an eye. 6.An apparatus according to claim 1 , wherein the first end of said needlecomprises a sharpened point.
 7. A method for injection comprising:placing a needle into a tissue, the tissue having a first surface and asecond surface defining a tissue thickness, at a penetration distance ofgreater than about the tissue thickness but such that even if extendedthe needle could not intersect the second tissue surface; and insertingan agent into the tissue through an outlet defined by a sidewall of theneedle, such that the agent exiting the outlet is in an orientationtowards one of the first and second surface of the tissue in said needlewhen the needle is placed into the tissue.
 8. A method for injecting anagent into a target tissue, the target tissue having a first surface anda second surface defining a tissue thickness, said method comprising:disposing a needle in an injection apparatus, the apparatus including asupport element, a needle guide platform disposed on said supportelement and having an external support surface and a channel extendingtherethrough, a needle disposed in said channel and movable along anaxis of injection through the channel, the needle having a first end anda second end and including a sidewall defining an outlet in the needleand an inlet disposed in the needle, the inlet being in fluid flowcommunication with the outlet; placing the needle in fluid flowcommunication with a medicament reservoir; positioning the injectionapparatus adjacent a tissue surface; advancing the needle outwardlythrough the channel; imbedding the needle into the target tissue suchthat the outlet is adjacent to, and oriented in a directionsubstantially facing, one of the first and second surface of the tissue;and transferring the agent into the tissue.
 9. A method according toclaim 8 , wherein the needle is imbedded into the target tissue at apenetration distance of greater than about the target tissue thickness.10. A method according to claim 9 , wherein even if the needle wereextended, it could not intersect the second target tissue surface.
 11. Amethod according to claim 9 , wherein the needle is imbedded into thetarget tissue at a penetration distance of about 1.5 mm to about 4 mm.12. A method according to claim 9 , wherein the needle is imbedded intothe target tissue at a penetration distance of about 2 mm to about 3 mm.13. A method according to claim 8 , wherein in the transferring step,the agent is transferred at a rate of about 1 to about 10microliters/second.
 14. A method according to claim 13 , wherein in thetransferring step, the agent is transferred at a rate of about 1 toabout 4 microliters/second.
 15. A method according to claim 14 , whereinin the transferring step, the agent is transferred at a rate of about 4microliters/second.
 16. An apparatus for injecting an agent into atissue comprising: a support element having a distal end and a proximalend; a needle guide platform disposed on the distal end of said supportelement and having an external support surface and a channel extendingtherethrough, the channel terminating in an aperture at the supportsurface; a needle disposed in said channel and axially movable throughsaid channel from a retracted position to an extended position, saidneedle having a first end and a second end, said needle including asidewall defining an outlet in said needle and an inlet disposed in saidneedle, the inlet being in fluid flow communication with the outlet,said needle extending from said aperture when moving from the retractedposition to the extended position; whereby, an axis of injection of saidneedle forms an acute penetration approach angle of up to about 60° witha tangent of the support surface at a point of intersection of alongitudinal axis of said needle with a projection of the supportsurface across the aperture.
 17. An apparatus according to claim 16 ,wherein the first end of said needle comprises a sharpened point.